New glutaconimides and their process of preparation



May 3 1960 J. REBEL l 2,935,512

' Naw GLu'rAcoRIMIDEs AND THEIR PRocEss or PREPARATION Filed rieb. 19,1958 r R,\ /coroczR5 H/ I \cN UD RzX (a) +PCL5 (4:)

R2/ \cN (Y) o R g/cooczri5 (YI) R1 R# I t-Mgl \COOC2H5 R2 o R o K R3 vR10 R 1 R. Rim-1121i( O N O O O 3. ,WxM//nlaw Arry i Panf O" 2,935,512New cLUrAcoNnnnEs AND man; Pnocnss '0F PREPARATION Joseph Redel, Paris,France, assigner to Chimie et Atomistique, Paris, France, ka French bodycorporate Application February 19, 1958, Serial No. 716,217 Claimspriority, application France February 22,- 1957 6 claims; (ci.260g/.231),V

` alkyl and notably lower alkyl, R3 ishydrogen, an alkyl radical, andnotably a lower alkyl, or an N-substituted or non-substitutedamino-alkyl radical, R4 is hydrogen or an alkyl radical and notably alower alkyl, and R is an alkyl radical, in particular a lower alkyl oran N-substituted or non-substituted amino-alkyl radical.

'I'hesenew compounds are of use as starting materials for the syntheticpreparation of'new active compounds. They moreover possess in themselvessedative, anticonvulsant and hypnotic properties of advantage in humanand veterinary medicine.

A further object of the invention is to provide a process of preparingsaid new compounds. Said process comprises condensing a di-substitutedcyanacetyl chloride having the formula:

AR1 C001 nz/ \ON with a substituted malonic acid ester having theformula:

' Coon R1, R2 and R4 having the aforementioned significations,thereafter cyclising the product ,thus obtained into substitutedv4-hydroxy-,glutaconimide, and thereafter treating theV4hydroxy1glutaconimide with at least one alkylating compound so as tointroduce at least the R5 substituent.

Fig. 2. of the accompanying drawings shows at (d), (e) and (f) theabovementioned stages lof the present process, which will be describedin detail hereinafter.'

The condensation of the disubstituted cyanacetylchloride (V) and of theester of the substituted malonic acid (VI), shown in the drawing to bediethyl ester, is efected by a reaction by means of magnesium, in themedium of an ether solvent.` It provides a substitutedcyanoacetyl-malonic acid diester (VII).

The cyclisation of this diester (stagee) is veffected by heating at thetemperature of the water bath with a mixture of acetic acid and sulfuricacid. -Thisprovides a 4-keto-glutarimide (VIIIa) which is in factexclusively 'present in its enolic form of 4hydroxyglutaconimide Thesubsequent stage (stage gf) is an alkylation reac tion, the compoundVIIIb being treated by at least an alkylating compound correspondingtothe alkyl radical it is desired to introduce; R3Y and RSZ designatingin 'the drawing such alkylating compounds which could be, for example,an alkyl sulfate, a diazoalkane, a halide vof N-substituted ornon-substituted -aminoalkyl and alcohol in the presence of amineralvacidsuch as HClor SO4H2,

2,935,512 Patented May 3, 2

ICS

5 possible-to simultaneously alkylate the two positions 1 v and 4 bymeans of the same alkylating compound, when R3 and R5 are identical, orto alkylate them successively with two alkylating compounds if R3 and R5are different.

The disubstituted cyanacetyl chlorides (V), lwhich are the startingpoint of the present process, are, in a general way, new and are alsoembraced by the scope of the invention as intermediate products. They canbeeasily obtained by reaction of the corresponding acid, if it isknown, with phosphorus'pentachloride. It could occur that the acidis newwhereas-some of its esters are known, in which case one of these esterswould be converted into acid before obtaining the `chloride of thelatter. When no known ester of the disubstituted cyanacetic acid isavailable, it is first necessary to prepare this ester syntheticallyfrom an ester of monosubstituted cyanacetic acid.

Fig. 2 shows at (a), (b) and (c) these auxiliary stages of the presentprocess.

Stage (a) is necessary in the least favourable 'case when only an esterof monosubstituted cyanacetic acid (Il), assumed to be ethyl ester, isknown as the starting point. This ester is then condensed with a halideRBX in the presence of sodium ethylate, which provides the disubstitutedester (III). Of course, in this stage R1 and R2 are interchangeable, thecompound II can con; tain the radical R2 instead of R1 and can be thencondensed with the halide RlX.

ln stage (b), the compound III obtained by means of stage (a) ordirectly, if it is known, isy hydrolyzed into the corresponding yacid(IV).

In stage (c), the acid (IV) is converted into acid chloride byphosphorus pentachloride.

The detailed examples described hereinafter illustrate the invention. Itmust be understood that the scope of the latter is not intended to belimited to these examples.

EXAMPLE 1 Preparation of 3jphenyl3ethyl-4-methoxyglutaconomid Ethylphenyl-ethyl-cyanacetate (Compound II[)\ g .109 Sodium hydroXideZ N v cc-550 Ethanol cc :5,50

The ethyl phenyl-ethyl-cyanacetate is obtained according t0 J. S:Chamberlain, J. Am. Chem. Soc. 1935, 57, 352.

After live minutes of contact it is diluted with 3.300 litres ofwaterand the unsaponiied part is extracted with ether. The aqueous phase isacidied in an ice bath and is extracted with distilled ether. Afterdrying, treating with carbon vblack and concentrating until dryness, 95g. of raw acid are obtained which, by slurrying inone volume ofdistilled petrol ether provides: 92 g. of acid (yield 97%) having amelting point of 56-57 C. and an acid number of 99.40-99.60%.

The reaction starts immediately and when it has calmed down there isadded:

Anhydrous bemene V cc-- 200 The mixture is left overnight at roomtemperature. It is filtered, the ltrate is treated with 20 cc. ofanhydrous acetone, concentrated in a vacuum and distilled. The fractiondistilling at 96-97 C. under a pressure of 0.6 of mercury is recovered,namely 102 g. of product (yield 91%). The product has the followingcharacteristics:

Boiling point 6 mm=96"97" C. Cl, percent=16.67% (theoretical:17.1%)

Stage (d) .--Ethyl 2-phenylK-2-ethyl-ayuno-malanni@ (Compound VII).-Thefollowing are introduced in a three-necked ask equipped with amechanical agitator, a `condenser and a dropping funnel:

Magnesium g 4 Ethyl malonate (Compound VI) g 26.2 Absolute ethanol ce9.6 Anhydrous ether cc, 135

The reaction is started olf by adding 1 cc. of carbon tetrachloride andthe mixture Yis reiluxed until the magnesium has disappeared. There arethen rapidly introduced with energetic agitation, so that the reflux ismain- 'tained spontaneously:

Phenyl-ethyl-cyanacetyl chloride g 34 Anhydrous ether cc-- 35 Stage(e).-3-phenyl-3-ethyl4hydroxyglutaconimide. The following are mixed in around-bottom flask:

Ethyl2-phenyl2ethyl2-cyanoacetyl-malonate g 82 Pure acetic acid rfc 82Concentrated sulfuric acid cc 82 The mixture is brought to 80 C. for onehour and 82 cc. of acetic acid added. Heating is continued at 80 for 30minutes (a total of 90 minutes). After cooling, the reaction mixture ispoured into 200 cc. of methanol in an ice bath and the whole is thenpoured into 2.500 litres of water. After filtering, washing untilneutral and drying, 57A g. of product are obtained. (Melting point=248249 C.)

By crystallization in methanol, the melting point rises to 252-253 C.Iand remains unchanged by successive crystallizations.

Analysis:

C, percent=67.2267.l2 (theoretical=67.5) H, percent=5.695.73(theoretical=5.63) N, percent=6.036.0l (theoretical=6.07) Enol, percent:100 (according to the Meyer method) Acid number=99.7l99.82%

Stage (f).-There is added to a solution of3-phenyl-3-ethyl-l-lttydroxy-glutaconimide g-- 4 Methanol cc-- 240 anether solution of diazomethane (which performs the function of thecompounds R5Z) prepared from 20 g. of nitrosomethylurea. Afterconcentrating until dryness, extracting with water, filtering theprecipitate and crystallizing it in 80% ethanol, 1.9 g. of product areobtained (yield: 45%) having the following characteristics:

M.P.==182-184 C. N, percent=5 .72-5 .76 (theoretical=5 .71

. 4 The melting point is not varied by successive crystallizations'inethanol. Analysis:

C, percent=68.5768.62 (calculated=68.6) H, percent=6.l7-6.25(calculated=6.12) N, percent=5.73-5.78 (calculated=5.7l)

EXAMPLE 2 Stages (b) to (e) are identical to those of Example l.

Stage (f).-There is added to a solution of:`l-phenyl-3-ethyl-4-hydroxy-glutaconixnide g 12.5 Potassium hydroxide6.6 N cc 24.5

while agitating:

Methyl sulfate (Compound R3Y) cc- 8 The mixture is allowed to react forhalf an hour and is thereafter brought to 100 C. for a few minutes.After cooling-and filtering, there is obtained: 0.3 g. of 1-methyl-3-phenyl-3-ethyl-4methoxy glutaconimide. The ltrate is acidied andfiltered; and there are thus obtained 13.2 g. of a precipitate which isrefluxed with 350 cc. of toluene. 'Ihe toluenic suspension is lteredhot. The insoluble part 1.5 g.) is constituted of the starting product.After concentration and cooling to ice cold, the filtrate provides the1-rnethyl-3-phenyl-S-ethyl-4-hydroxy-glutaconimide: 8.4 g. (M.P.=157-158C.). By successive erystallizations in ethanol, the melting point isbrought to a constant value, namely 15S-159 C.

Analysis:

C, percent=68.36-68.2l (theoretical=68.6) H, percent=6.316.24(theoretical=6.12) N, percent=5.685.75 l(theoretical=5.7l) Enol,percent=% (Meyer method) The following mixture is refluxed whileagitating for l0 minutes;1-methy-3-phenyl-3-ethyl-4-hydroxyglutaconimide g-- 2.5 Sodium hydroxidecc-.. 8 Methyl sulfate cc 2 After leaving overnight and filtering theprecipitate formed, 1.9 g. ofl-methy1-3-phenyl-3-ethyl-4-methoxyglutaconimide are obtained:M.P.=124125 C.

By acidification of the filtrate there is vrecovered 0.55 g. of startingproduct, representing a yield of 94%.

By successive crystallzations in ethanol, the melting, point is broughtto a constant value, namely 129-130 C.

Analysis:

C, percent=69.4069.51 (calculated=69.5) H, percent=6.666.66(calculated=6.50) N, percent==5.395.43 (calcu1ated=5.41) Enol, percent=0(Meyer method) 'EXAMPLE 3 Magnesium g 1.1 Ethyl methyl-malonate(compound VI) g 8 Absolute ethanol vc 3.2 Anhydrous ether cc 25 Thereaction is started olf by adding a little carbon tetrachloride and isreuxed until the vmagnesium has Y .5 completely disappeared.`'Ihereaftenl the following are added while energetically agitatin'gso'as to maintain a spontaneous reflux:

Chloride of phenyl-ethyl-cyanacetyl V -g 9.5 Anhydrous ether cc--malonate g- 11.7 Pure acetic acid ce 12 Concentrated sulfuric acid cc-..12

The mixture is brought to 90 C. in a water bath for six hours and pouredinto ice-cold water. The precipitate formed is then filtered and washeduntil neutral, providing 7.6 g. of product (yield 91%), M.P.=190l95 C.By crystallization in 80% ethanol, the melting point is brought to aconstant value, namely: 198-200 C.

Analysis:

C, percent=67.9168.02 (calcu1ated=68.60) H, percent==6.166.13(calculated=6.l2) N, percent=5.605.67 (calculated-:5.71)

Stage (f).-To the following solution:

3 phenyl 3 ethyl- 4 hydroxy 5 methyl glutaconimide E Potassium hydroxide7.82 N --.-cc-- 39 there is added while agitating:

Methyl sulfate 29.7

The mixture is allowed to react until neutral. It is then alkalinizedwith several drops of potassium hydroxide, rendered ice cold, andfiltered. 4.6 g. of product are obtained having an M.P. of 142-144 C.

By acidification of the filtrate 1.5 g. of initial product are obtainedcorresponding to a yield of 87%.

By successive crystallizations in ethanol and sublimation under vacuumthe melting point'is brought to a constant value, namely M.P.=l45146 C.

Analysis:

C, percent, 69.90-70.01 (theoretical 70.3) H, percent 6.97-6.94(theoretical 6.96) N, percent, S29-5.31 (theoretical 5.13)

EXAMPLE 4 Preparation of1-methyl-3-phenyl-3ethyl-4-beta-dethylaminoethoxy-glutaconimide(COmPOUDd I, R1=C6H5, R2=C2H5,

R3=CH3, R4=H, R5=CH2CH2N C2H5)2 The starting product isl-methyl-3-phenyl-3-ethyl-4- hydroxy-glutaconimide obtained in Example2. The following are put into a three-necked flask equipped with amechanical agitator, a dropping funnel and a condenser:

Absolute ethanol cc 120 Sodium g 1.2

When everything has dissolved, the following is added:

3 ethyl 4 hydroxyy glutaconimide 12t7Whenthere'is'f'complete"dissolutionfthe following is added: v

Chloride of beta-diethylamino-ethyl The mixture is then reuxed for sixhours and left overnight. The sodium chloride formed is filtered and thefiltrate is concentrated in a vacuum. The residue is distilled withether, washed with diluted sodium hydroxide, and then with water untilneutral.

By acidification of the aqueous phase, filtering and washing of theformed precipitate, 2.5 g. of the starting product which did not react,are recovered.

By drying and concentration until dryness of the ether phase, the baseis obtained in the form of a syrupy liquid constituting 10.3 g. ofproduct having a base number which is 99.43% of the theoretical number.The base is purified in the form of its acid oxalate prepared in thefollowing manner:

10 g. of raw base are dissolved in 70 cc. of acetone and treated with:

(compound Crystallized oxalic acid g-- 3.8 Acetone cc-.. 30

The oxalate precipitates immediately. It is filtered (11.5 g.) andcrystallized into 30 cc. of 95% ethanol. After rendering ice-cold andfiltering, the purified acid oxalate is obtained (10.5 g., M.P.=133-136C.) whence the base is obtained in the usual manner.

By successive crystallizations, the melting point of the acid oxalate isbrought to a constant Value, namely 136- 137 C.

Analysis:

C, percent=60.7660.68 (calculated=60.82) H, percent=7.047.08(calculated=6.9l) N, percent=6.65-6.64 (calculated=6.45)

EXAMPLE 5 Preparation of 3.3-diethyl-4-methoxy-gluzaconimide Stage(b).-Dethylcyanacetic acid (Compound IV). -The following are mixed in anErlenmeyer iiask:

Ethyl diethyl-cyanacetate g-- 77 Sodium hydroxide 2 N cc-- 350 Ethanolcc 350 Boiling point 0 3 mm =108-l 10 C. Melting point=6264 C.

Stage (cy-Chloride of diethyl-cyanacetyl (Compound V).-The Vfollowingare mixed:

Diethyl-cyanacetic acid g-- 54 Phosphorus pentachloride g The reactioncommences immediately; when it has calmed down, there are added:

Anhydrous benzene cc-- 15 0 and the mixture is left overnight at roomtemperature. The mixture is filtered, the filtrate is treated with 20cc. of anhydrous Vacetoneconcentrated in a vacuum and 15 distilled. Theproduct distilling under a pressure of 20 '7 mm. of mercury at971,-;972QA C., is obtained, namely 52' g. (yield 86%). Thecharacteristics are as follows: Y

Stage (d).-Ethyl 2.2-dietlzyI-Z-cyauo-acelylmao/zate (Compound VIl).-Thefollowing are put in a threenecked ask equipped with a mechanicalagitator, a condenser and a dropping funnel:

Magnesium g 6.15 Ethyl malonate (Compound VI) g 40.5 Ethanol cc 17.6Anhydrous ether cc-- 150 The reaction is started off by addition of'lcc. of carbon tetrachloride yand reuxed until all the magnesium hasdisappeared. There is then introduced under energetic agitation and atsuch speed that the reflux is maintained spontaneously: l

Chloride of dierhyi-'cyanacetyl g 4o Anhydrous ether cc 50 Retiuxing ismaintained ten minutes after the end of the introduction. After cooling,the mixture is decomposed with 150 cc. of ice-cold 10% hydrochloricacid, extracted with ether, and the ether phase is washed successivelywith hydrochloric acid and then water. After drying, concentrating anddistilling, 29 g. of product are obtained corresponding to the fractionhaving a B.P.0.7 mm.=139140 C.

Stage (e).-3.3-a'iethyl-4-hydroxy-glutaconmide.-The following are mixedin a round-bottom ask:

Ethyl 2.2-diethyl-2-cyano-acetylmalonate g 40 Pure acetic acid cc 40Concentrated sulfuric acid cc 40 The mixture is put in a water bathfortwo hours in the course of which a decarboxylation is observed. lItis then poured into ice-cold water, filtered, and the precipitate formedis washed, which precipitate weighs 18 g. and melts at 219 C.

By crystallization in 80% ethanol, the melting point rises to 223-224 C.and remains unchanged by successive crystallizations.

Analysis:

C, percent=58.90-59.00 (theoretical=59.0) H, percent=7.107.16(theoretical=7.10) N, percent=7.577.60 (theoretical=7.65)

Stage (f).-The following solution is reuxed for tive hours under abubbling of dry hydrochloric gas:

3.3-diethyl-4-hydroxy-glutaconimide g 35.8 Methanol cc 250 It `is thenconcentrated until dry, the residue is distilled with diluted sodiumhydroxide, and the solution obtained is treated with carbonio gas; themethoxy derivative precipitates (25.5 g.).

The pure product is obtained by crystallization in ethanol.

C, percent, 60.75, 60.73; calculated 60.9 H, percent, 7.67, 7.68;calculated 7.62 N, percent, 6.91, 6.91; calculated 7.07

By acidification of the aqueous mother lies of the raw product 11.2 g.of the starting product are obtained.

EXAMPLE 6 Preparation of 3.3-diethyl-4-methoxy-5-metl1yl-glutacoumide(Compound I, R1=R2=C2H5, R3=H, R4:R5=CH3) Stages (a) to (e) may bededuced from those of Example 5.

Stage (f). -14.1 gr. of 3.3-diethyl-4-hydroxy-5fmethylg glutaconirnideare dissolvedin 60 ce. of methanol and this' solution isi treated withan ether solution of diazomethane prepared from 30 g. ofnitrosomethylurea When effervescence has ceased it is concentrated untildry and -the residue is treated with diluted sodium hydroxide, extractedwith ether so as to eliminate an insoluble and the aqueous fraction isprecipitated by the carbonio gas. The O-methylated derivativeprecipitates (6.7 g.); by crystallization in ethanol the pure product isobtained:

C, percent, 62.67, 62.50; calculated 62.6 H, percent, 8.05, 8.12;calculated 8.06 N, percent, 6.64, 6.69; calculated 6.64

EXAMPLE 7 Preparation of 3-phenyl-3-methyl-4-methoxy glulaconmde Stage(at-Ethyl pheuyl-methyl-cyanacetate (Compound III).-The following areput in a three-necked ilask equipped with a mechanical agitator, adropping funnel and a condenser:

Absolute ethanol cc 500 Sodirun g 19.6

then, when the sodium has disappeared, the following is added:

Ethyl phenyl-cyanacetate (Compound Il) g 161 then the the following isadded:

Methyl iodide (Compound RZX) g The mixture is heated, while agitating,to 28-30 C. (interior temperature) until neutral (half an hour). Aftercooling, the sodium -iodide formed is filtered and the filtrateconcentrated in a vacuum. The residue is dis tilled'with ether andwashed with sodium bicarbonate, with diluted sodium bisulvte, and thenwith water until neutral, and dried.

-After concentration and distillation, there is obtained the fractionhaving a B.P.15 mm =147149 C., whence there are obtained 152 g. ofproduct (yield 88%) whose saponiiication number is: 99.17% to 99.03% `ofthe theoretical number.

Stage (b).--Phenylmethyl-cyanacetc acid (Compound IV).-The following aremixed in an Erlenmeyer flask:

Ethyl phenyl-methyl-cyanacetate g 100 Sodium hydroxide 2 N cc-- 485Ethanol at 95 cc 485 Phenyl-methyl-cyanacetic acid Q Phosphoruspentachloride g The reaction starts immediately. When it has calmeddown, there is added:

Anhydrous benzene cc and the mixture is left overnight at roomtemperature. It is then filtered and the filtrate treated with 20 cc. ofanhydrous acetone, -concentrated in a vacuum anddistilledmhmrgslupt,sitllaa under a Pressure Qf 08 mm. of cercury at10S-104 C. is` obtained, namely 72 g. of product (yield 91%) having aB.P.,6 mm,=9697" C.

Stage (d).-Ethyl 2phenyl-methyl2-cyanoacetylmal ouate (CompoundVI1).-The following are put into a three-necked ask equipped with amechanical agitator, a condenser and a dropping funnel:

Magnesium g-- Ethyl malonate (Compound VI) g-- 32.9 Ethanol cc 14.5Anhydrous ether cc 150 The reaction is started by adding 1 cc. of carbontetrachloride and is refluxed until all the magnesium has disappeared.The following are then added under energetic agitation and at speed sothat the reux is maintained spontaneously:

Phenyl-methyl-cyanacetyl chloride g-- 40 Anhydrous ether cc-- 50 Ethyl2phenyl2methyl2-cyano-acetylmalonateg-.. 29 Concentrated sulfuric acidcc 29 Pure acetic acid cc..- 29

The mixture is put in a water bath for 90 minutes and is then pouredinto ice-cold water. The precipitate formed (17 g.) is filtered andwashed.

By crystallization in ethanol, the melting point is brought to 252-253C. and remains unchanged by successive crystallizations.

Analysis:

C, percent=66.1266.25 (theoretical 66.4) H, percenm5.265.27 (theoretical5.07) N, percent=6.46 (theoretical 6.46)

Stage (f).-The following solution is reliuxed for five hours under abubbing of dry hydrochloric acid:

3phenyl3-methyl-4-hydroxy-glutaconimide l g' 3 5 Methanol cc-- 1,050

A-fter treatment identical to that-of Example 5, the desired derivative(32 g.) is obtained; the following pure product is obtained bycrystallization in ethanol:

C, percent, 67.30, 67.37; calculated 67.5 H, percent, 5.70, 5.63;calculated 5.63 N, percent, 6.01, 6.12; calculated 6.07

By acidiiication of the aqueous mother lies of the raw product, 1 g. ofthe starting product is recovered.

EXAMPLE 8 Stages (b) to (e) are identical to those of Example 3.

Stage (f).-5 g. of 3-phenyl-3-ethyl-4-hydroxy-5-methyl-glutaconimide aredissolved in 50 cc. of methanol, and an ether solution of diazomethaneprepared from 25 g. of nitrosornethylurea is added. When theeffervescence has ceased, the mixture is concentrateduntil dry, theresidue is treated with sodiumhydroxide, a Vslight insoluble part iseliminated 'by ltration and the filtrate is precipitated-with CO2. -3.5lg. of the-required product Y 10 are obtained. By crystallization inethanol, the pure product is obtained.

M.P.=140141 C. C, percent, 69.53, 69.45 (calculated 69.5) H, percent,6.58, 6.68 (calculated 6.56) N, percent, 5.50, 5.47 (calculated 5.41)

Stages (b) to (e) are identical to those of Example 1. Stage (jy-Thefollowing solution is refiuxed for six hours under a bubbling of dryhydrochloric acid:

3-phenyl-3ethyl-4-hydroxyglutaconimide g-- 20 Ethanol cc-.. 600

After a treatment identical to that of Example 5, there are obtained15.5 g. of the required product which is purified by crystallization inethanol.

C, percent, 69.27, 69.32 (calculated 69.5) H, percent, 6.66, 6.70(calculated 6.56) N, percent, 5.39, 5.43 (calculated 5.41)

By acidification of the aqueous mother lies of the raw product, 5.1 g.of the initial product are recovered.

EXAMPLE 10 Preparation of 3-pheny[-3ethyl-4-propoxy-glutaconimde Stages(b) to (e) are identical to those of Example 1. Stage (f).-The followingsolution is reuxed for six hours with bubbling of dry hydrochloric gas:

3-phenyl-3-ethyl-4-hydroxyglutaconimide g-.. 19.1 Propanol (n) cc 600After a treatment identical to that of Example 5, 14 g. of the requiredproduct are obtained and are purified by crystallization in 80% ethanol.

C, percent, 70.40, 70.44 (calculated 70.3) H, percent, 6.99, 7.04(calculated 6.96) N, percent, 5.07, 5.11 (calculated 5.13)

By acidification of vthe aqueous mother lies of the raw product, 6.2 g.of the starting product are recovered.

EXAMPLE 11 Preparation of 3-phenyl-3-ethyl-4-butoxyglutaconmde Stages(b) to (e) are identical to those of Example l. Stage (f).-The followingsolution is reiiuxed for six hours with bubbling of dry hydrochloricgas:

3-pheny1-3ethy1-4-hydroxy-glutaconimide g-- 25 Butanol (n) cc-.. 500

After a treatment identical to that of Example 5, 22.9 g. of therequired product are obtained and are purified by crystallization in`70% ethanol.

C, percent, 71.00, 70.89 (calculcated 71.08) H, percent, 7.42, 7.46(calculated 7.32)

N, percent, 4.92, 4.97 (calculated 4.88)

By a'cidication of Ithe aqueous mother lies of the raw product,vv 6.2 g.of the starting product are recovered.

EXAMPLE 12.

Stage (a).-Ethyl phenyl-propyl-cyanacetate (Compound III).-The followingare put in a three-necked fiask equipped with a mechanical agitator, adropping funnel and a condenser:

Absolute ethanol cc- 500 Sodium g 18.9

When the sodium has disappeared, the following is added:

Ethyl phenylcyanacetate (Compound III) g 155 Then the following isadded:

n-Propyl bromide (Compound RZX) g-.. 121

Ethyl phenyl-propyI-cyanacetate g 10 Sodium hydroxide 2 N cc-- 43Ethanol (95) cc-- 43 After 35 minutes of contact and then diluting with360 cc. of water, the unsaponified part is extracted with ether. Theaqueous phase is acidified in an ice-bath and is extracted withdistilled ether. After drying, treating with carbon black andconcentrating until dry, there are obtained 8 g. oflphenyl-propyl-cyanacetic acid (yield 97%), M.P.=9496 C., acidnumber=98.97-98.80%.

Stage (c).-Phenyl-propyl-cyanacetyl chloride (Compound V) .-Thefollowing are mixed:

Phenyl-propyl-cyanacetic acid g-.. 113 Phosphorus pentachloride g-- 173The reaction starts immediately. When it has become calm, there isadded:

Anhydrous benzene cc-.. 200

The mixture is left overnight at room temperature. The mixture isfiltered and the filtrate is treated with 20 cc. of anhydrous acetone.After concentrating in a vacuum and distilling, there is obtained thefraction distilling under a pressure of 1.5 mm. of mercury at 109-110C., namely 108 g. of product (yield 91%). The product has a B.P.0,8 mm=103-104' C.

Stage (d).-Ethyl Z-phenyl-2-propyl-2-cyano-acetylmalonate (CompoundVlI).-The following are put into a three-necked flask equipped with amechanical agitator, a dropping funnel and a condenser:

Magnesium g.. 4.4 Ethyl malonate (Compound VI) ....g-- 28.9 Absoluteethanol cc-- 17.9 Ether N* 150 The reaction is started with 1 cc. ofcarbon tetrachloride and refiuxed until all the magnesium hasdisappeared. 'I'he following are then added while energeticallyagitating at speed so that the reflux is maintained spontaneously:

Phenyl-propyl-cyanacetyl chloride ..g 40 Anhydrous ether fr 50 Therefluxing is continued for ten minutes after the end of introduction.After cooling, the mixture is decomposed by 150 cc. of ice-cold 10%hydrochloric acid, extracted with ether and the ether phase is washedsuccessively with 10% hydrochloric acid and then water. After drying,concentrating and distilling, there is obtained the fraction having aB.P. 2 mm,=164-165 C., namely 33 g. of product (yield=53%).

Stage (e).-3 phenyl 3 propyl 4 hydroxy glutaconz'mide.-The following aremixed in a roundbottom flask:

Ethyl 2-phenyl-2-propyl-2-cyanoacetyl malonate g 10 Concentratedsulfuric acid cc-- 10 Pure acetic acid cc-.. 10

The mixture is brought to C. for 90 minutes and then 10 cc. of aceticacid are added. The heating is continued at 80 for a further 2 hours (atotal of 3 hours 30 minutes) and the mixture is then poured intoice-cold water. The precipitate formed is filtered and washed untilneutral and represents 6.5 g. of product (yield 92%), M.P.=250 C.

By crystallization in ethanol, the melting point is brought to Z55-256C. and remains unchanged by successive crystallizations.

Analysis:

C, percent==68.1568.11 (theoretical 68.6) H, percent==6.176.26(theoretical 6.12) N, percent=5.69-5.70 (theoretical 5.71) Stage(f).-The following are refluxed for five hours with a bubbling of dryhydrochloric gas:

3-phenyl-3-propyl-4-hydroxy-glutaconimide g 5.5 Methanol cc After atreatment identical to that of Example 5, 4.2 g.

of the required product are obtained and purified by crystallization inethanol.

C, percent 69.34, 69.44, (calculated 69.5) H, percent, 6.52, 6.63,(calculated 6.56) N, percent, 5.31, 5.37, (calculated 5.41)

By acidification of the aqueous mother lies of the raw product, 1 g. ofthe starting product is recovered.

EXAMPLE 13 Preparation of 3-phenyl-3-propyl4ethoxyglutaconmde (CompoundI, R1=C5H5, R2=C3H7, R3=R4=H, R5=C2H5) Stages (a) to (e) are identicalto those of Example 12. Stage (f).-The following solution is reliuxedfor 5 hours with bubbling of dry hydrochloric gas:

3-phenyl-3-propyl-4-hydroxy-glutaconimide g 20 Ethanol cc 600 After atreatment identical to that of Example 5, 15.2 g. of the requiredproduct are obtained and purified by crystallization in 80% ethanol.

M.P.=124-125 C.

C, percent, 70.09, 70.12 (calculated 70.3) H, percent, 6.89, 6.90(calculated 6.96) N, percent, 5.08, 5.17 (calculated 5.13)

By acidification of the aqueous mother lies of the raw product, 5.6 g.of the starting product are recovered.

EXAMPLE 14 Preparation of 3-phenyl-3-propyl-4-butoxy-glulaconmde(Compound I, R1=C6H5, R2=C3Hq, R3=R4=H,

Stages (a) to (e) areidentical to those of Example 12.

y13 Stage (f).-The following solution is reuxed for 5 hours withbubbling of dry hydrochloric gas:

3-phenyl-3-propyl-4-hydroxyglutaconimide g. 17 Butanol (n) fr' 500 Aftera treatment identical to that of Example 5, 16 g. of the requiredproduct are obtained and purified by crystallization in 70% ethanol.

C, percent, 71.50, 71.45 (calculated 71.76) H, percent, 7.79, 7.85(calculated 7.64)

N, percent, 4.63, 4.65 (calculated 4.65)

By acidiiication of the aqueous mother lies of the raw product, 3.5 g.of the starting product are recovered.

EXAMPLE Preparation of 1-methyl-.3-aliethyl-4-methoJcy-glutacanimide(Compound I, R1=R2=C2H5, R=CH3, R4=H, Raf-CH3) The compound obtained inExample 5 is the starting product.

Added to the following solution:

3.3-diethyl-4-methoxy-glutaconimide g 13.6 Sodium hydroxide N cc..- 136are 12.2 cc. of methyl sulfate and the mixture'is left 12 hours Whileagitating at room temperature. Thereafter, the mixture is filtered and14.3 g. of the required product are obtained and purified bycrystallization in hexane.

C, percent, 62.76, 62.68 (calculated 62.6) H, percent, 8.19, 8.17(calculated 8.06) N, percent, 6.45, 6.46 (calculated 6.64)

EXAMPLE 16 Preparation of 1.5-dmethyl-3.3-dethyl-4-methoxyglutaconimdeThe compound obtained in Example 6 is the starting product.

Added to the following solution:

3.3-diethyl-4-methoxy-5methylglutaconimide g 3.2 Sodium hydroxide N-cc-- 30.4

are 2.8 cc. of methyl sulfate and the mixture is left 5 hours Whileagitating at ordinary temperature. Thereafter, the mixture is filteredand 3.1 g. of the required product are obtained and purified bycrystallization in petrol ether.

C, percent, 64.21, 64.06 (calculated 64.00) H, percent, 8.62, 8.66(calculated 8.44) N, percent, 6.22, 6.15 (calculated 6.22)

EXAMPLE 17 Preparation of 1. i-dimethyl-3-phenyl-4-methaxyglutaconimide(COmPOUDd I, R1=CH3, R2=C3H5, R3=CH3, R=H, Rs=CH3) The compound obtainedin Example 7 is the starting product.

Added to the following solution:

3-phenyl-3-methyl-4methoxyglutaconimide g.- 2.2 Sodium hydroxide N -cc19 are 1.85 cc. of methyl sulfate and the mixture is left half an hourwhile agitating at room temperature. Thereafter, the mixture is filteredand 2.2 g. of the required product are obtained 'and .purified bycrystallization in ethanol.

C, percent, 68.68, 68.61 (calculated 68.6)

H, percent, 6.20, 6.15 (calculated 6.12) N, percent, 5.70, 5.67(calculated 5.71)

vEXAMPLE 18 Preparation of ,I.3-de1hyl-3-phenyZ-4methoxyglutuc0n mide(Compound I, R1=C2Hs, R2=CeH5, Ra=C2H5, R4=H, R5=CH3) .The compoundobtained in Example 1 is the starting product.

Added to the following solution:

3phenyl3-ethyl-l-methoxy-glutaconimide g-- 15.7 Sodium hydroxide N cc132 EXAMPLE 19 R1=C3H5, R2=C2H5, R3=CH3, RFH. R5=C2Hn Thecompoundobtainedin Example 9 is the starting product.

Added to a hot solution (65 C.) of:

3-pheny1-3-ethy1-4-ethoxy-glutaconimide g 14.3 Sodium hydroxide N cc 113are 10.4 cc. of methyl sulfate, while agitating during a quarter of anhour so that the temperature does not exceed C. Thereafter 64 cc. ofsodium hydroxide N are added and the mixture is left overnight whileagitating between 50 and 65 C. and then rendered ice-cold and filtered.14.7 g. of the required product are thus obtained and are purilied bycrystallization in hexane.

C, percent, 70.05, 70.12 (calculated 70.3) H, percent, 6.98, 7.03(caulculated 6.96) N, percent, 5.16, 5.15 (calculated 5.13)

EXAMPLE 20 Preparation of I-dimethylaminoethyl-.-phenyl-3ethyl4-methoxy-glutaconimide The compound obtained in Example 1 is thestarting product.

Added to the following solution:

Sodium g 3.3 Absolute ethanol cc-.. 200

are:

3phenyl3-ethyl-4-methoxy-glutaconimide g 16 followed by:

Hydrochlorate of (beta-dimethylamino) ethyl chloride g 11.3

The mixture is refluxed for hours whilefagitating. The reaction liquidis then poured into a large volume of water and filtered .17 g. of asolid white product are thus Vobtained and are dissolved in hydrochloricacid, treated with carbon black and precipitated with sodium hydroxide.After ltering, 15.2 g. of the desired product are obtained and arepurified by crystallization in isopropylic ether.

C, percent, 68.29, 68.35 (calculated 68.35) H, percent, 7.59, 7.60(calculated 7.59) N, percent, 8.78, 8.74 (calculated 8.86)

EXAMPLE 21 Preparation of1-methyl-3-phenyl-.propyl-4-methoxyglutaconmide The compound obtained inExample 12 is the starting product.

Added to the following solution:

3-phenyl-3-p-ropyl-4-methoxy-glutaconimide g-- 15.6 125 are 12 cc. ofmethyl sulfate, the mixture is left while agitating 12 hours at roomtemperature and then filtered. 16.5 g. of the desired product are thusobtained and are purified by crystallization in ethanol C, percent,70.10, 70.28 (calculated 70.3) H, percent, 6.96, 7.04 (calculated 6.96)N, percent, 5.00, 5.12 (calculated 5.13)

Sodium hydroxide N cc 16 Having now described my invention what I claimas new and desire to secure by Letters Patent is:

1. As new compounds: substituted glutaconimides having the formula:

in which R1 and R2 are'each a radical selected from the group consistingof phenyl and lower alkyl radicals, R3 is a radical selected from thegroup consisting of hydrogen, lower alkyl radicals, lower aminoalkylradicals and lower aminoalkyl radicals substituted at the N atom bylower alkyl radicals, R4 is a radical selected from the group consistingof hydrogen and lower alkyl radicals, and R5 is a radical selected fromthe group consisting of lower alkyl radicals, lower arninoalkyl radicalsand lower aminoalkyl radicals substituted at the N atom by lower alkylradicals.

2. 3-phenyl-3-ethyl-4-methoxy-glutaconimide.

3. 1-methy1-3-phenyl-3-ethyl-4-methoxy-glutaconimide.

4. 3phenyl-3-methyl-4-methoxy-glutaconimide- 6.3-phenyl-3-propyl-4ethoxyglutaconimide.

Beilstein: Hand. der. Org. Chem., vol. 2, p. 589, 4th Ed. (1920).

1. AS NEW COMPOUNDS: SUBSTITUTED GLUTACONIMIDES HAVING THE FORMULA